The Journal of neuroscience : the official journal of the Society for Neuroscience
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The function of Ric-3, which is required for nicotinic acetylcholine receptor (nAChR) expression in C. elegans, is unclear. Here we found that Ric-3 can promote or inhibit cell-surface delivery of alpha-bungarotoxin-binding nAChRs (BgtRs) composed of alpha7 subunits. At low levels, Ric-3 promoted BgtR assembly, endoplasmic reticulum (ER) release, and cell-surface delivery without trafficking from the ER. ⋯ At low levels, Ric-3 interactions are short-lived and promote BgtR assembly and ER release. At higher levels, Ric-3 interactions are longer-lived and mediate ER retention. In neurons, Ric-3 ER retention appears to promote transport within the dendritic ER subcompartment, thereby restricting alpha7 trafficking to dendrites and preventing axonal transport.
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Activity-dependent gene expression mediating changes of synaptic efficacy is important for memory storage, but the mechanisms underlying gene transcriptional changes in age-related memory disorders are poorly understood. In this study, we report that gene transcription mediated by the cAMP-response element binding protein (CREB)-regulated transcription coactivator CRTC1 is impaired in neurons and brain from an Alzheimer's disease (AD) transgenic mouse expressing the human beta-amyloid precursor protein (APP(Sw,Ind)). Suppression of CRTC1-dependent gene transcription by beta-amyloid (Abeta) in response to cAMP and Ca(2+) signals is mediated by reduced calcium influx and disruption of PP2B/calcineurin-dependent CRTC1 dephosphorylation at Ser151. ⋯ Inhibition of calcium influx by pharmacological blockade of L-type voltage-gated calcium channels (VGCCs), but not by blocking NMDA or AMPA receptors, mimics the decrease on CRTC1 transcriptional activity observed in APP(Sw,Ind) neurons, whereas agonists of L-type VGCCs reverse efficiently these deficits. Consistent with a role of CRTC1 on Abeta-induced synaptic and memory dysfunction, we demonstrate a selective reduction of CRTC1-dependent genes related to memory (Bdnf, c-fos, and Nr4a2) coinciding with hippocampal-dependent spatial memory deficits in APP(Sw,Ind) mice. These findings suggest that CRTC1 plays a key role in coupling synaptic activity to gene transcription required for hippocampal-dependent memory, and that Abeta could disrupt cognition by affecting CRTC1 function.
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Effective navigation and locomotion depend critically on an observer's ability to judge direction of linear self-motion, i.e., heading. The vestibular cue to heading is the direction of inertial acceleration that accompanies transient linear movements. This cue is transduced by the otolith organs. ⋯ Instead, they depended similarly on movement direction in head coordinates (better performance in the horizontal plane) and on body orientation (better performance in the upright orientation). Heading thresholds were correlated with, but significantly larger than, predictions based on sensitivity in the coarse discrimination task. Simulations of a neuron/anti-neuron pair with idealized cosine-tuning properties show that heading thresholds larger than those predicted from coarse direction discrimination could be accounted for by an amplitude-response nonlinearity in the neural representation of inertial motion.
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In vivo regeneration of peripheral neurons is constrained and rarely complete, and unfortunately patients with major nerve trunk transections experience only limited recovery. Intracellular inhibition of neuronal growth signals may be among these constraints. In this work, we investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during regeneration of peripheral neurons in adult Sprague Dawley rats. ⋯ Moreover, following severe nerve transection injuries, local pharmacological inhibition of PTEN or siRNA knockdown of PTEN at the injury site accelerated axon outgrowth in vivo. The findings indicated a remarkable impact on peripheral neuron plasticity through PTEN inhibition, even within a complex regenerative milieu. Overall, these findings identify a novel route to propagate intrinsic regeneration pathways within axons to benefit nerve repair.
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While ubiquitous, pharmacological manipulation of consciousness remains poorly defined and incompletely understood (Prys-Roberts, 1987). This retards anesthetic drug development, confounds interpretation of animal studies conducted under anesthesia, and limits the sensitivity of clinical monitors of cerebral function to intact perception. Animal and human studies propose a functional "switch" at the level of the thalamus, with inhibition of thalamo-cortical transmission characterizing loss of consciousness (Alkire et al., 2000; Mashour, 2006). ⋯ A specific reduction in activity within the putamen was noted and further investigated with functional connectivity analysis. Progressive failure to perceive or respond to auditory or noxious stimuli was associated with a reduction in the functional connectivity between the putamen and other brain regions, while thalamo-cortical connectivity was relatively preserved. This result has not been previously described and suggests that disruption of subcortical thalamo-regulatory systems may occur before, or even precipitate, failure of thalamo-cortical transmission with the induction of unconsciousness.